Local Anesthetic Mechs

Cocaine discovery, 1860

• Albert Niemann

• coca shrub: reversibly numbed his tongue

• Freud became aware and thought it would be useful for morphine addiction

1884

• Koller

• first eye surgery using cocaine as local anesthetic

Novocaine (procaine)

• 1905

• Alfred Einhorn

• first synthetic ester-type local anesthetic

• nerve blocking properties without CNS actions of cocaine

Xylocaine (lidocaine)

• 1943

• first amide-type local anesthetic

Structural components of all local anesthetics

• aromatic ring

• connecting group (ester or amide)

• ionizable amine group

Ester-linked local anesthetics are hydrolyzed to

• carboxylic acid

• alcohol

• in presence of water and esterases

  • very easily

Which have a longer duration of action, amide or ester local anesthetics?

amide-linked (are not as easily hydrolyzed)

Ester-type local anesthetics

• procaine

• cocaine

• tetracaine

• benzocaine

• dimethocaine

Amide-type local anesthetics

• lidocaine

• bupivacaine

• mepivacaine

• articaine

• prilocaine

Chemical properties of local anesthetics that determine activity

• lipid solubility

• ionization constant (pKa)

Are local anesthetics weak acids or bases?

• bases

• proportion of free base and salt forms depends on pH and pKa of amino group

Weakly acidic drugs (pKa under 7)

Lipid solubility determines…

• potency

• plasma protein binding

• duration of action of local anesthetics

Difference between Analgesics and Local Anesthetics

• analgesics: specific inhibitors of pain pathways

• local anesthetics: non-specific inhibitors of peripheral sensory, motor, and autonomic pathways

  • inhibit conduction of action potentials in ALL afferent and efferent nerve fibers, usually in PNS

What is often administered with short or medium acting local anesthetics to reduce blood flow to the area?

• Vasoconstrictors (epinephrine)

What does administering a vasoconstrictor with local anesthetics do?

• reduces blood flow to the area of injection

• slows the area of removal

• increases duration of action

• increases concentration of local anesthetic around nerve sites

• decreases systemic circulation and toxicity

• may lead to tissue ischemia (if vasoconstriction too high)

How are ester-linked local anesthetics metabolized?

• tissue and plasma esterase

• pseudocholinesterases

• excreted via kidney

How are amide-linked local anesthetics metabolized?

• liver CYP450

• metabolites returned to circulation and excreted via kidney

Dosage forms of local anesthetics

• topical

• infiltration

• iontophoresis

• peripheral nerve block

• central nerve block

• intravenous

Procaine (Novacain)

• short acting ester-linked

• low hydrophobicity

• 1st synthetic local anesthetic

• metabolite: para-aminobenzoic acid (PABA) is a known allergen

  • can exacerbate bacterial infections

• used for infiltration anesthesia for dental procedures, diagnostic nerve block

Cocaine

• ester-linked

• naturally occurring

• first anesthetic to be discovered

• primary use: ophthalmic anesthetic and part of TAC (tetracaine, adrenaline, cocaine)

• cardiotoxicity and potential abuse limits therapeutic use